2-tertiary-aminomethyl-nu-(loweralkyl) anilines



3,383,415 2-TERTllARY-AMINOMETHYL-N-(LOWER- ALKYDANILINES Philip M. Carabateas, Schodack, N.Y., assignor to Sterling Drug Inc, New York, N.Y., a corporation of Delaware No Drawing. Qriginal application Aug. 17, 1964, Ser. No. 390,218. Divided and this application May 15, 1967, Ser. No. 638,610

2 Claims. (Cl. 260-570.9)

ABSTRACT OF THE DHSCLOSURE 2-[N (lower alkyl)-N'-R -aminomethyl]-N-(loweralkyl)-N-Ac-anilines where R is lower-alkenyl, halo- (lower-alkenyl) or (lower-cycloalkyl)-(loWer-alkyl) and Ac is hydrogen, lower-alkanoyl or lower-alkanesulfonyl, found to be analgesic antagonists and anticonvulsants, are prepared by various means, e.g., by reacting an N-(loweralkyl)-isatoic anhydride with a secondary amine, NH(R )(lower-alkyl), reducing the resulting 2-(loweralkylamino)-N-(lower-alkyl)-N-R -benzamides to form the above compounds where Ac is hydrogen and acylating the latter to obtain said compounds where Ac is loweralkanoyl or lower-alkanesulfonyl.

This invention relates to compositions of matter of the class of anilines and, in particular, to 2-aminomethylaniline derivatives.

This application is a division of my copending application Ser. Nov 390,218, filed Aug. 17, 1964.

The invention in one aspect resides in the concept of a composition having a molecular structure in which a 2- aminomethylaniline is doubly substituted on the nuclear amino group by lower-alkyl and by lower-alkanoyl or lower alkanesulfonyl, and, also, is doubly substituted on the other amino group by lower-alkyl and by loweralkenyl, halo-(lower-alkenyl), phenyl-(lower-alkyl) or (lower-cycloalkyl)-(1ower-alkyl). In another composition aspect of the invention, the molecular structure is as already stated except the nuclear (or anilino) amino group is monosubstituted by lower-alkyl.

Among the compounds of my invention are those f Formula I where R is lower-alkyl, Ac is hydrogen, lower-alkanoyl or lower-alkanesulfonyl, R is loWer-alkyl, and R is loweralkenyl, halo-(lower-alkenyl), phenyl-(lower-alkyl) or (lower-cycloalkyl)-(lower-alkyl). Optionally, the benzene ring can be substituted in any of its four remaining positions by low-molecular substituents, e.g., halo, loweralkyl, lower-alkoxy, benzyloxy, lower-alkylmercapto, lower-alkanoylamino, nitro, hydroxy, lower-alkanoyloxy, and the like, and, where more than one substituent is present, they can be the same or different and they can be in any of the various position combinations relative to each other. The halo substituents include chloro, bromo, iodo and fiuoro.

The term lower-alkyl, as used herein, e.g., as the meaning for R and R in Formula I, means alkyl radicals having from one to six carbon atoms and is illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, n-amyl, isoamyl, n-hexyl, 3-hexyl, and the like.

States Patent 3,383,415 Patented May 14, 1968 The term lower-alkenyl, as used herein, e.g., as one of the meanings for R in Formula I, means alkenyl radicals having from three to six carbon atoms and is illustrated by 2-propenyl (allyl), 2-methyl-2-propenyl, 3- methyl-Z-butenyl, 3-buteny1, 2-hexenyl, and the like.

The term halo-(lower-alkenyl), as used herein, e.g., as one of the meanings for R in Formula I, means haloalkenyl radicals having from three to six carbon atoms and from one to two halo substituents (i.e., chloro, brorno, iodo and fluoro, preferably chloro and bromo), and is illustrated by The term lower-alkanoyl, as used herein, e.g., as one of the meanings for A in Formula I, means alkanoyl radicals having from one to six carbon atoms, illustrated by formyl, ethanoyl (acetyl), n-propanoyl (propionyl), n-butanoyl (butyryl), Z-methyl-n-butanoyl, n-hexanoyl, and the like.

The term lower-alkanesulfonyl, as used herein, e.g., as one of the meanings for Ac in Formula 1, means alkanesulfonyl radicals having from one to six carbon atoms, illustrated by methanesulfonyl, ethanesulfonyl, npropanesulfonyl, 2-propanesulfonyl, n-butanesulfonyl, 2- butanesulfonyl, n-hexanesulfonyl, and the like.

The term lower-cycloalkyl, as used in the term (lower-cycloalkyl)-(lower-alkyl), one of the meanings for R in Formula I, means cycloalkyl radicals having from three to six carbon atoms, illustrated by cyclopropyl, cyclobutyl, cyclopentyl and cyclo-hexyl.

Compounds of Formula I are prepared by various procedures. A three-step procedure utilizing N-(loWer-alkyD- isatoic anhydrides is given as follows: In step (1) an N-(lower-alkyl)-isatoic anhydride (II) is reacted with a secondary amine of the formula H-NR R (HI) to yield a 2 (lower alkyl)amino-N-R -N-R -benzamide (IV), which in step (2) is reduced, preferably with lithium aluminum hydride, to form a 2-(N'-R -N'-R -aminomethyl)-N-(lower-alkyl)aniline (Ia). In step (3) the aniline (Ia) is acylated to yield the corresponding N-acyl derivative (Ib). This procedure is illustrated structurally as follows:

where R and R have the meanings given above for Formula I, R is lower-alkenyl, phenyl-(lower-alkyl) or (lower-cycloalkyl)-(lower-alkyl), and Ac is loweralkanoyl or loWer-alkanesulfonyl, and the benzene ring can be substituted by groups which are unreactive under reaction conditions used in the procedure, e.g., loweralkyl, lower-alkoxy, benzyloxy, and the like. Where R is halo-(lower-alkenyl) or where the benzene ring has nuclear substituents sensitive to reaction conditions in individual steps, e.g., halo, nitro, or lower-alkylmercapto compounds in step (2) or hydroxy compounds in step (3), the compounds of the invention are readily obtained by other procedures described below.

Compounds of Formulas Ia and Ib having-OH substituents on the benzene ring are prepared by converting the corresponding compounds of Formula Ia bearing an -'OCH or -OCH -phenyl substituent into the corresponding --OH compound, and then selectively :acylating (step 3) with one molar equivalent quantity of acylating agent to form the compound of Formula Ib having the --OH substituent.

Another procedure for the preparation of the compounds of my invention is as follows: A 2-[N-(loweralkyl) -N-acylamino]-benzaldehyde (V) is reacted in step (1) with a primary amine of the formula H N-R to yield corresponding N R 2 [N' (lower-alkyl) N acylamino] benzalamine (VI), which is reduced in step (2), preferably with sodium borohydride, to yield an N-R -Z- [N' (lower alkyl) N acylamino] benzylamine (VII); and, in step (3) the benzylamine (VII) is alkylated, using a lower-alkyl halide or, optionally for compounds of Formula Ia where R is methyl, a mixture of formaldehyde and formic acid, to yield my N-R -N-R 2 [N (lower alkyl) N Ac amino] benzylamine of Formula Ib where R and R have the meanings given above for Formula I and Ac (or acyl) is lower alkanoyl or lower-alkanesulfonyl. This procedure thus is suited for the preparation of compounds having reactive or sensitive nuclear substituents, e.g., nitro, halo or (lower-alkyl)mercapto, and of compounds where R is halo-(lower alkenyl). Illustrative of this procedure is the following preparation: benzyloxy 2 (N ethyl N propionylamino)benzaldehyde is reacted with 3 chloro 2 propenylamine to yield N (3 chloro 2 propenyl) 5 benzyloxy 2 (N' ethyl N propionylamino)benzalamine, which is reduced with sodium borohydride to yield N-(3-chloro-2-pr0penyl)-5-benzyloxy-2-(N' ethyl-N'-propionylamino)benzylamine, which, in turn, is reacted with a mixture of form-aldehyde and formic acid to produce N (3 chloro 2 propenyl) N methyl 5 benzyloxy 2 (N' ethyl N propionylamino)benzylamine, alternatively named N-[2-(N'- 3 chloro 2 propenyl N methylaminomethyl) 4 benzyloxyphenyl] N ethylpropionamide; treating the benzyloxy compound with concentrated hydrochloric acid yields the corresponding hydroxy compound, i.e., N (3 chloro 2 propenyl) N methyl 5 hydroxy-2-(N'- ethyl N propionylamino)benzylamine or N-[2-(N-3- chloro 2 propenyl N methylaminomethyl) 4 hydroxyphenyl] N ethylpropionamide. The intermediate 5 benzyloxy 2 (N ethyl N propionylamino) benzaldehyde is obtained in five steps as follows: reacting 5 benzyloxy 2 nitrobenzaldehyde with ethylene glycol to form the ethylene acetal of 5 benzyloxy 2 nitrobenzaldehyde, reducing the nitro group by catalytic hydrogenation using Raney nickel catalyst, reacting the resulting ethylene acetal of 2 amino 5 benzyloxybenzaldehyde with propionic anhydride to form the ethylene acetal of 5 benzyloxy 2 propionylaminw benzaldehyde, alkylating the latter by reaction with ethyl iodide in the presence of potassium carbonate and treat ing the resulting 5 benzyloxy 2 (N ethylpropionylamino)benzaldehyde ethylene acetal with concentrated hydrochloric acid to form the intermediate aldehyde.

Another procedure for the preparation of the compounds of my invention is given as follows: In step (1) a 2 methylnitrobenzene (IX) is reduced to a 2 methylaniline (X); in step (2) the aniline (X) is alkylated with a lower-alkyl halide or, for compounds where lower-allay is methyl, with a mixture of formaldehyde and formic acid, to yield an N"(lower-alkyl)-2-methylaniline (XI), which in step (3) is acylated to yield an N-(acyl)-N- (lower-alkyl)-2-methylaniline (XII); in step (4) compound XII is brominated with N-brornosuccinimide to yield 2 [N acyl N (lower alkyl)amino]benzyl bromide (XIII); and, finally in step (5) the bromide (XIII) is reacted with a secondary amine of the formula HNR R to produce an N-R -N-R -2-[N-acyl-N-(lower alkyl)amino]benzylamine (Ib) where R and R have the meanings given for Formula I and acyl" is lower alkanoyl or loWer-alkanesulfonyl. Illustrative of this procedure is the following preparation: reduction of 5- chloro-2-methylnitrobenzene to yield S-chloro-Z-methylaniline; reaction of the aniline with formaldehyde and formic acid to yield N methyl 5 chloro 2 methylaniline; acylation of the latter with propionyl chloride to produce N methyl N propionyl 5 chloro 2 methylaniline; reaction of the latter with N-bromosuccinimide to yield N methyl N propionyl 2 bromomethyl-S- chloroaniline; and, reacting the bromomethyl compound with N-ethylallylamine to produce N [2 N'-allyl-N- ethylaminomethyl) 5 chlorophenyl] N methylpropionamide.

The compounds of Formulas I, Ia and lb are useful both in free base form and in acid-addition salt form and both forms are within the purview of the invention, and are considered to be one and the same invention. The acid-addition salts are simply a usually more convenient form for use; and, in practice, use of the salt form inherently amounts to use of the base form. The acids which can be used to prepare the acid-addition salts are preferably those which produce, when combined with the free base, pharmacodynamically acceptable salts, that is, salts whose anions are relatively innocuous to the animal organism in pharmacodynamic doses of the salts, so that the beneficial properties inherent in the free base are not vitiated by side effects ascribable to the anions; in other words, the latter do not substantially affect the pharmacodynamic properties inherent in the cations. In practicing my invention, I found it convenient to employ the hydrochloride salt. However, other appropriate pharmacodynamically acceptable salts within the scope of the invention are those derived from mineral acids such as hydrobromic acid, hydriodic acid, nitric acid, phosphoric acid, sulfamic acid, and sulfuric acid; and organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, methanesulfonic acid, ethanesulfonic acid, quinie acid, and the like, giving the hydrobromide, hydriodide, nitrate, phosphate, sulfamate, sulfate, acetate, citrate, tartrate, lactate, methanesulfonate, ethanesulfonate and quinate, respectively.

The acid-addition salts are prepared preferably by reacting the free base and acid in an organic solvent, e.g., ethanol, in which case the salt separates directly or can be obtained by concentration of the solution.

Although pharmacodynamically acceptable salts are preferred, all acid-addition salts are Within the scope of my invention. All acid-addition salts are useful as sources of the free base form even if the particular salt per se is not desired as the final product, as for example when the salt is formed for purposes of purification or identification, or when it is used as an intermediate in preparing a pharmacodynamically acceptable salt by ion exchange procednres.

The compounds of Formulas Ia and lb have pharmacodynamic properties, e.g., the compounds of Formula Ib are useful as antagonists of strong analgesic agents, e.g., meperidine, and the compounds of Formula Ia are useful as anticonvulsants in addition to being useful as intermediates -for the preparation of the acylated compounds of Formula lb.

The molecular structures of the compounds of my invention are established by their mode of synthesis and corroborated by the correspondence of calculated and found values for the elementary analyses and by infrared ('IR) spectral analyses.

The following examples will further illustrate the invention without, however, limiting it thereto.

- Example 1 The intermediate 2-alkylamino-N-R -N-R -benzamides (Formula IV) were prepared by reacting an N-(loweralkyl)-isatoic anhydride (Formula II) with a secondary amine (Formula HI), HNR R illustrated as follows:

(A) 2 methylamino-N-cyclopropylrnethyl-N-methylbenzamide was prepared as follows: To a solution con taining 67.6 g. of N-methylisatoic anhydride in 25 ml. of ether was added over a thirty minute period 35 g. of N- methylcyclopropylmethylamine. The resulting mixture was then heated on a steam bath for two hours, allowed to stand overnight, and taken up in 500 ml. of ether. The ether solution was filtered to remove a small amount of insoluble material, the filtrate evaporated in vacuo, and the resulting oily material distilled in vacuo to yield 77 g. of Z-methylamino N-cyclopropylmethyl N-methylbenzamide, B.P. 110-1 13 C. at 0.16 mm., n =1.567 1. A 10.9 g. portion of this amine was dissolved in ether, an excess of hydrogen chloride in ether was added, the resulting white gummy precipitate was triturated with acetone to yield a solid, and the solid was recrystallized from methyl ethyl ketone to yield 3.6 g. of Z-methylamino-N- cyclopropylmethyl N methylbenzamide hydrochloride, M.P. 149.'150.0 C. (corn).

The above intermediate N-methylcyclopropylmethylamine was prepared as follows: A suspension containing 26.4 g. of lithium aluminum hydride and 400 ml .of ether was stirred for ninety minutes to form a solution of the hydride. To this solution was added 61.8 g. of N- methylcyclopropanecarboxamide in 100 ml. of ether at a rate suflicient to cause refluxing. The reaction mixture was then stirred for five hours at 30 C. and allowed to stand overnight. To the reaction mixture was added carefully 27 ml. of water and the mixture was stirred for one was combined with the above oily amine product, dried over potassium hydroxide pellets and distilled. There was thus obtained 38.5 g. of N-methylcyclopropylmethylamine, B.P. 9'2-96 at 760 mm., n -=1.4210. For further purification, the amine was redistilled to yield 35.3 g. of purified product, B.P. 94-96" at 760 mm., n =l.4209.

(-B) Z-methylamino N allyl-N-methylbenzamide was prepared as follows: 28.4 g. of N-methylallylamine was added to g. of N-methylisatoic anhydride. After the vigorous reaction with the evolution of carbon dioxide, the mixture gradually became liquid and was then refluxed gently with stirring for about thirty minutes and then allowed to cool. The mixture was distilled in vacuo to yield 58. 8 g. of the product, Z-methylamino-N-allyl N- methylbenzamide, Bi. 119-121" C. at 0.2 mm., HD2951?- 1.5715.

(G) 2-ethylamino-N-allyl-N-methylbenzamide was prepared following the p-rocedure described in Example 1A using 50.4 g. of N-ethylisatoic anhydride, 75 ml. of ether, 211.3 g. of N-methylallylamine, and a reflux period of three hours. There was thus obtained 40.8 g. of the product, 2-ethylamino-N-allyl-N-methylbenzamide, RP. 95-- 98 C. at 0.07 mm. n =l.5596.

(D) Q-methylamino-N-allyl N-ethylbenzamide was prepared following the procedure described in Example 1A using 53 g. of N-methylisatoic anhydride, 5 0 ml. of ether and 29.8 g. of N-ethylallylamine, and a reflux period of four hours. There was thus obtained 61.1 g. of the product 2,-methylamino-'N-allyl-N-ethylbenzamide, B.'P'. 102- 105 C. at 011 mm., n =l.5598.

Following the procedure described in Example 1% and using corresponding molar equivalent quantities of the appropriate Q-N'(lower-alkyl)-isatoic anhydride II) and secondary-amine, H-NR R (H 1), the compounds of Table A can be prepared.

The intermediates used to prepare the compounds of Table A are generally known and are prepared by conventional methods.

hour, followed by addition of g. of potassium hydroxide flakes and additional stirring for two hours. The solid ll 0 R1 TABLE A Q R R1 2 1G 4-C2H5 11-C4H9 I1-C4H9 CH CH-CH aawmn 11-0111 c2115 onion-on, 4-OCH C2H5 ll-CsHw CHaCHCHg 5-OC4Ho-Il CH3 CH3 Cfig-phenyl 4 C0113 C2115 CzHs (CHm-phenyl 4-CH 01H CH CHz-cyclopropyl C111 CH; (OHsh-oyclohexyl CzH5 czHa CHzC(CH3)-CH2 n-CsH1 CixHa OHZCHZCH-CH2 CH3 n-O H CHzCH-CH2 pzHs CzHa CHaCH-CH: 1-C3H7 CH3 CHzCH-CHz are aaea aa tfi 3 4 9 CH eomo C211 c2115 onion-0H: m 3 4-OCH5 C 115 C2115 CHZCH-OHB 5-OCH3 CQHfi CH3 CHzCH-CH: 1X 4-OCHC5H5 CzHs C2H5 CHaCH-CHg Example 2 was filtered off and washed with ether. The filtrate and the washings were combined and ether was removed by distillation to leave the oily amine product. In order to recover additional amine product which distilled with the ether, the ether distillate was extracted with dilute aqueous hydrochloric acid; the extract was concentrated in vacuo; the residue was azeotroped first with ethanol-benzene and then benzene to yield a white solid; the solid was taken up in 25 ml. of water; and, the aqueous solution was treated with potassium hydroxide pellets with The 2-(N-R -N-R -aminomethyl)-N-R-anilines (Formula Ia) of the invention were prepared by reducing, preferably with lithium aluminum hydride, the intermediate 2-RNH-N'-R -N'-R -benzamides (Formula IV) of Example 1, illustrated as follows:

(A) 2- N '-cyclopropylmethyl-N-methylaminomethyl) N-methylaniline was prepared as follows: A suspension containing 22.6 g. of lithium aluminum hydride in 250 ml. of tetrahydrofuran was stirred for one hour and then to cooling and then extracted with ether. The ether extract this suspension was added at a rate to cause the solvent to reflux 66 g. of Z-methylarnino-N-cyclopropylmethyl-N- methylbenzamide. The reaction mixture was then refluxed for six and one half hours and allowed to stand overnight. To the reaction mixture was added cautiously 23 ml. of water followed by 70 ml. of potassium sodium tartrate. The mixture was stirred for one hour and filtered, and the precipitate washed with tetrahydrofuran. The combined filtrate and washings were concentrated in vacuo, and the resulting oily residue was distilled in vacuo to yield 51.2 g. of the product, 2-(N-cyclopropylmethyl-N- methylaminornethyl)-N-methylaniline, B.P. 73-75 C. at 0.1 mm., n ==1.5360. A 10.2 g. sample of the product was treated with excess hydrogen chloride in ether to yield a white gummy material which was triturated with isopropyl alcohol to yield a solid. The solid was recrystallized from ethanol to yield 7.3 g. of 2-(N-cyclopropylmethyl N methylaminomethyl) N methylaniline dihydrochloride, M.P. 188.8189.2 C. (corn) with decomposition.

(B) 2 (N' allyl N methylarninomethyl) N- methylaniline was prepared following the procedure described in Example 2A using 58.3 g. of Z-methylamino-N- allyl-N-methylbenzamide, 22.8 g. of lithium aluminum hydride and 300 ml. of tetrahydrofuran. There was thus obtained 44.4 g. of the product, B.P. 6973 C. at 0.1 mm., n ":1.5312.

(C) 2 (N' allyl N methylaminomethyl) r ethylaniline was prepared following the procedure described in Example 2A using 40.5 g. of 2-ethylamino-N- allyl-N-methylbenzamide, 14.2 g. of lithium aluminum hydride and 300 ml. of tetrahydrofuran. There was thus obtained 33.3 g. of the product, B.P. 7175 C. at 0.17 mm., n =1.5209. A g. portion of this compound was converted into 11.7 g. of its dihydrochloride, M.P. 180-182 C. with decomposition.

(D) 2 (N' allyl N ethylaminomethyl) N methylaniline was prepared following the procedure described in Example 2A using 60.2 g. of Z-methylamino-N-allyl-N- ethylbenzamide, 20.9 g. of lithium aluminum hydride and 400 ml. of tetrahydrofuran. There was thus obtained 47.5 g. of the product, B.P. 80-85 C. at 0.1 mm.,

Following the procedure described in Example 2A and using corresponding molar equivalent quantities of the appropriate 2-alkylamino-N'-R -N-R -benzamide (IV) and lithium aluminum hydride, the compounds of Table B can be prepared.

CHa-N TABLE 13 n-C 4H CgHs -CsHra Example 2U 4-0 CH3 2V 5'OCH2C6H5 pionic anhydride and the appropriate 2-(N'-R -N-R aminomethyl)-N-(lower-all;yl)aniline; for example, the reaction of propionyl anhydride with Example 2T yields N [2 N allyl N ethylaminomethyl) 5 methoxyphenyl] -N-ethylpropionamide.

Example 3 N [2 (N' allyl N methylaminomethyl)phenyl]- N-methylacetamide was prepared as follows: To 19.0 g. of 2 (N' allyl N methylarninornethyl) N methylaniline was added 15.3 g. of acetic anhydride and the resulting solution was allowed to stand for three hours. To the reaction mixture was added ml. of methanol and the resulting solution was concentrated in vacuo. The remaining oil was taken up in chloroform; the chloroform solution washed successively with 10% aqueous sodium hydroxide solution and water, and then distilled in vacuo to remove the chloroform. The remaining oil was distilled in vacuo to yield 15.7 g. of the product, N-[2-(N-allyl- N-methylaminomethyl phenyl] -N-rnethylacetamide, B .P. 87-93 C. at 0.15 mm., l2 :1.5125. The product was converted in to its hydrochloride salt as follows: It was dissolved in ml. of methyl ethyl ketone, an excess of hydrogen chloride in ether was added, and the mixture was boiled on a steam bath for twenty minutes to remove the excess hydrogen chloride and then allowed to cool. The crystalline solid that separated slowly on standing was collected and recrystallized twice from methyl ethyl ketone to yield 7.1 g. of N-[2-N-allyl-l l'-methylaminomethyDphenyl}-N-methylacetarnide hydrochloride, M.P. 150.5152.8 C. (corn).

Example 4 N [2 (N-allyl-N-methylaminomethyl)phenyl]-N- methylpropionamide was prepared following the procedure described in Example 3 using 13.2 g. of 2-(N :allyl-N-methylaminomethyl)-N-methylaniline and 13 g. of propionic anhydride. The product in free base form distilled at 90-95 C. at 0.08 mm. and 12.0 g. of its hydrochloride salt, M.P. l63.4-165.0 C. (corn), was oh tained after one recrystallization from methyl ethyl ketone and ether.

Example 5 N [2 (N'-cyclopropylmethyl-N-methylaminomethyl)-phenyl]-N methylpropionamide was prepared as follows: To a solution containing 20.4 g. of 2-(N'-cyclopropylmethyl N'methylaminomethyl) -N-methylaniline dissolved in ml. of chloroform was added slowly a solution containing 9.25 g. of propionyl chloride in 50 ml. of chloroform. After resulting mixture had stood for two hours, the chloroform was removed by distilling in vacuo. The remaining oily material was dissolved in water; the aqueous solution made alkaline with 35% aqueous sodium hydroxide solution; the alkaline solution extracted with ether; and, the ether extract washed with water and concentrated in vacuo to remove the ether. The remaining oil was dried azeotropically with benzene. The resulting oil was distilled in vacuo to yield 23.0 g. of the product, N [2 (N' cyclopropylmethyl-Nmethylaminomethyl) phenyl]-N-methylpropionamide, B.P. 103-407 C. at 0.1 mm., n =1.5209. The product was purified by conversion into its picrate salt by treating 21. 2 g. of it with 19 g. of picric acid dissolved in ethanol. The solution was concentrated to a volume of about 150 ml. and cooled. The resulting precipitate crystallized and was recrystallized from ethanol to yield the picrate salt, M.P. 132-133 C. The picrate was reconverted into the free base as follows: It was heated with a mixture of 225 ml. of 10% aqueous hydrogen chloride .and 150 ml. of benzene. The aqueous acidic solution was separated and then made alkaline with potassium carbonate and 35% aqueous sodium hydroxide solution. The alkaline solution was extracted with ether, the ether extract distilled in vacuo to remove the ether, and the remaining oil dried azeotropically by adding benzene and distilling it off in vacuo. The resulting oil was distilled in vacuo to yield 15.0 g. of purified N-[2-(N'-cyclopropylmetl1yl-N'-methylaminomethyl) phenyl] -N-methylpropionamide in free base form, B.P. 101-103 C. at 0.1 mm., n =1.5199.

Example 6 N [2 (N' allyl N' ethylaminomethyDphenyl]- N-methylpropionamide was prepared following the procedure described in Example 3 using 47.5 g. of 2-(N- allyl-N-ethylaminomethyl)-N-methylaniline and 58.5 g. of propionic anhydride. There was thus obtained 48.6 g. of N [2 (N' allyl-N-ethy1aminomethyl) phenyl]-N- methylpropionamide, -B.P. 108112 C. at 0.1 mm., n =1.S078. The picrate was prepared as in Example 5 using 43 g. of picric acid in 200 ml. of hot ethanol; the picrate melted at 11912l C. after two recrystallizations from ethanol. The picrate was decomposed as in Example 5 to yield 35.1 g. of N-[2-(N'-allyl-N-ethylaminomethyl) phenyl]-N-methylprpionamide in free base form, B.P. 110-111 C. at 0.2 mm., n =1.5070.

Example 7 N [2 (N'-allyl-N'-methylaminomethyl)phenyl]-N- ethylpropionamide was prepared following the procedure described in Example 3 using 33.3 g. of 2-(N-a1lyl-N'- methylaminomethyl)-N-ethylaniline and 25 ml. of propionic anhydride. There was thus obtained 30 g. of N- [2 (N-allyl-N-methylaminomethyl)phenyl]-N-ethylpropionamide, B.P. 107-110 C. at 0.3 mm., n =1.5069. The product was converted into its p-toluenesulfonate as follows: To a solution containing the base in 100 ml. of ethanol was added 21.8 g. of p-toluenesulfonic acid monohydrate, the reaction mixture concentrated in vacuo to remove the solvent, the remaining oily material triturated with ethyl acetate to yield a white solid, and the solid recrystallized twice from methyl ethyl ketone to yield 31.3 g. of N-[2-N'-allyl-N'-methylaminomethyl)phenyl]- N-ethylpropionamide p-toluenesulfonate, M.P. 132.8- 135.0 C. (corn).

Example 8 N [2 (N'-allyl-N'-methylaminomethyl)phenyl] N- ethylbutyramide is prepared following the procedure described in Example 5 using corresponding molar equivalent quantities of 2-(N-allyl-N-methylaminomethyl) N- ethyl-aniline and butyryl chloride.

Example 9 N [2 (N-al1yl-N'-methylaminomethyl)-5-methoxyphenyl]-N-ethylpropionamide is prepared following the procedure described in Example 7 using corresponding molar equivalent quantities of 2-(N'-.allyl-N'-methyl- 10 aminomethyl)-5-methoxy-N-ethylaniline and propionic anhydride.

Example 10 N [2 (N allyl-N-methylaminomethyl)-4-rnethoxyphenyl] N- ethylpropionamide is prepared following the procedure described in Example 7 using corresponding molar equivalent quantities of 2-(N'-allyl-N-mcthylaminomethyl)-4-methoxy N-ethylaniline and propionic anhydride.

Example 11 N [2 (N' allyl-N'-methylaminomethyl) 5 hydroxy-phenyl]-N-ethylpropionamide is formed following the procedure described in Example 7 using molar equivalent quantities of 2-(Neallyl-N methylaminomethyl)-5- hydroxy-N-ethylaniline and propionic anhydride. 2-(N'- allyl-N-methylaminomethyl) -5-hydroxy-N-ethylaniline is prepared by demethylation of 2-(N'-allyl-N'-methylaminomethyl) 5 methoxy-N-ethylaniline by heating it with concentrated hydrobromic acid in glacial acetic acid.

Example 12 N [2 (N allyl-N'-methylarninomethyl)phenyl]-N- ethylethanesulfonamide is prepared following the procedure described in Example 5 using 2-(N'-allyl-N'-methylaminomethyl)-N-ethylaniline and a molar equivalent quantity of ethanesulfonyl chloride in place of propionyl chloride. Similarly, using methanesulfonyl chloride, npropanesulfonyl chloride, Z-butanesulfonyl chloride or nhexanesulfonyl chloride in place of ethanesulfonyl chloride, there is obtained a corresponding N-[2-(N'-allyl-N'- methylaminomethyl) phenyl] -N-ethyla1kanesulfonamide.

Example 14 N-[Z-(N' allyl N rnethylaminomethyDphenyl]-N- ethylformarnide is prepared by adding a slight excess of chloral to a solution of 2-(N'-allyl-N'-methylaminomethyD-N-ethylaniline and heating the reaction mixture for about fifteen minutes on a steam bath. The product is obtained by distilling oil? in vacua the chloroform and excess chloral.

Example 15 N-[2-(N' allyl N methylaminomethyl)phenyl]-N- ethylcaproamide is prepared following the procedure described in Example 5 using corresponding molar equivalent quantities of 2-(N'-allyl-N'-met-hylaminomethyl)-N- ethylaniline and caproyl chloride.

Example 16 N[2-(N 3 chloro 2 propenyl-N'-methylaminomethyl) -5-chlorophenyl] -N-ethylacetamide is prepared by reacting N-(Z-bromomethyl 5 chlor0phenyl)-N-ethylacetamide with N-methyl-3-chloro-2-propenylamine. The intermediate N-(2-bromomethyl-5-chlorophenyl)-N-ethylaceta mide is obtained in two steps by alkylating S-chloroo-acetotoluidide with ethyl iodide and then brominating the resulting N-ethyl-S-chloro-o-acetotoluidide with N- bromosuccinimide.

Example 17 N-[Z-(N' 3 chloro 2 propenyl-N' methylaminomethyl)phenyl]-N-ethylpropionamide is prepared by re acting N-(2 bromomethylphenyl)-N-ethylpropionamide 1 1 with N-lmethyl-3-chloro-2-propenylamine. The intermediate N-(2-br0mo-methylphenyl)-N-ethylpropionamide is obtained by brominating N-ethyl-o-propionotoluidide with N-bromosuccinimide.

Compounds of Formula Ib prepared as described in the foregoing examples were found to .be antagonists of strong analgesics. Thus, when tested in rats by a modified DArmour-Srnith test procedure, they were found to be antagonists of the analgesic activity of meperidine. In this test procedure, when the compounds of this invention were administered prior to or simultaneously with ad ministration of meperidine, the expected analgesic effect of the latter was decreased with increasing dosage levels of the former to a point where no analgesic eifect was obtained. And when the new compounds were administered after the administration of meperidine, the analgesic eifect was diminished or terminated, depending on the dosage levels involved. For example, compounds of this invention, each in the form of an aqueous solution of an acid-addition salt, were administered subcutaneously to rats to determine the dosage level, in terms of weight of antagonist per kilogram of body weight of the animal, which caused reduction of the analgesic effect of a 60 mg/kg. dose of meperidine hydrochloride by approximately 50 percent (AD Illustrative AD values are 32 mg./kg. for N-[2-(N-allyl-N"methylaminomethyl) phenyl]-N-methyl-acetamide as its hydrochloride, 20 -mg./ kg. for N-[Z-(N allyl N methylaminomethyl) phenyl]-N-met-hylpropionamide as its hydrochloride, and 32 mg./kg. for N-[2-(N-allyl-N--methylaminomethyl) phenyl]-N-ethylpropionamide as its p-toluenesulfonate.

Compounds of Formula Ia have been tested by standard pharmacological evaluation procedures and found to possess anticonvulsant properties, for example, they protect against metrazol induced convulsions in mice, e.g., the

calculated does (ED of 2-(Ncyclopropylmethyl-N- methylaminornethyl)-N-methylaniline as its dihydrochloride for protecting 50% of the animals against convulsions induced by metrazol (50 mg./kg. i.v.) was found to be 39.2:93 mg./kg. by intraperitoneal administration.

I claim:

1. A compound of the formula where R and R are each lower-alkyl and R is loweralkenyl, halo-(lower-alkenyl) or (lower cycloalkyl)- (loweralkyl) 2. 2-(N' cyclopropylmethyl-N'-rnethylaminomethyl)- N-methylaniline according to claim 1 where R and R are each methyl and R is cyclopropylmethyl.

References Cited UNITED STATES PATENTS 3,112,344 11/1963 HorrOrn et al. 260--570.'9 X 3,153,093 10/1964 Horrorn et a1 260570.5

OTHER REFERENCES Braun et al.: Ann, vol. 445, pages 201-5 and 209-13 1925) CHARLES B. PARKER, Primary Examiner.

ROBERT V. HINES, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,383,415 May 14, 1968 Philip M. Carabateas It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 13, "-CH CH=CHA" should read -CH CH=CHI line 22, "A" should read Ac lines 50 to 55, Formula IV should appear as shown below:

C-N u Column 6, Table A, Examples 1G, 1H, 11, IF, 1Q, 1R, 1U, 1V, 1W, and 1X under heading R ,"CH CH-CH each occurrence,

should read (IH CH -CH same Table, Example 1N, under heading R "CH C(CH )-CH should read CH C(CH )=CH same Table A, Example 10, under heading R "CH CH CH-CH should read CH CH CH=CH same Table A, Example 1T, under 2 under headlng "CH2CH-CH(CH2)2CH3" should read CH CH=CH(CH CH same Table A, Example 1U, under heading Q, "6-CH O" should read 6--CH Column 7, Table B,

Examples E, 2F, 26, 2N, 20, 2P, 2S, 2T, 2U, and 2V under heading R "CH CH-CH each occurrence, should read CH CH=CH same Table B, Example 2L, under heading R "CH C(CH )-CH should read CH C(CH )=CH same Table B,

Example 2M, under heading R "CH CH CH-CH should read 2i. CH CH CH=CH same Table B, Example 2R under heading u u R CH CH CH(CH CH should read CH CH CH(CH CH Column 10, line 52, "in vacua" should read in vacuo Column 11, line 30, "32 mg./kg." should read 3.8 mg./kg.

Signed and sealed this 6th day of January 1970."-

(SEAL) Attest:

EDWARD M.FLETCI-IBR,JR. WILLIAM E. SHCUYLER, JR.

' Attesting Officer Commissioner of Patents 

